The present invention generally relates to the area of mass spectroscopic analysis, and more particularly relates to mass spectrometer apparatus, including a multi-reflecting time-of-flight mass spectrometer (MR TOF MS) and a method of use.
Time-of-flight mass spectrometers (TOF MS) are increasingly popular—both as stand-alone instruments and as a part of mass spectrometry tandems with another TOF (TOF-TOF), with a quadrupole filter (Q-TOF), or with an ion trap (ITMS-TOF). They provide a unique combination of high speed, sensitivity, mass resolving power (hereinafter called resolution) and mass accuracy. Even higher resolution and mass accuracy are desired for analysis of complex mixtures, typical for applications in biotechnology and pharmaceuticals.
The introduction of multi-reflecting and multi-turn schemes has recently led to substantial improvement of the resolution of time-of-flight mass spectrometers.
Before continuing, it will be useful to define some terms used throughout this document. As used herein, a “planar multi-reflecting time-of-flight mass analyzer” is a device that comprises two elongated ion mirrors, which are preferably grid-free. Ions are reflected between the ion mirrors while slowly drifting in the direction of elongation of the ion mirrors (the “drift direction”).
“Aberrations” means expansion coefficients for spatial or time-of-flight deviations caused by spread in the initial ion parameters.
“First order focusing” corresponds to the compensation of the first derivative of an output parameter (at the output of the device) per linear variation of the input parameter. First order expansion coefficients are often referred to as “linear coefficient” or “first derivative.” First order focusing may include “first order time-of-flight focusing with respect to ion energy,” “first order time-of-flight focusing with respect to spatial coordinates,” “first order spatial focusing,” and “first order spatial per energy focusing,” which are discussed below.
“First order time-of-flight focusing with respect to ion energy” corresponds to compensation of the time of flight T derivative per ion energy k, i.e., dT/dk=T|k=0. Devices that perform such compensation are referred to as “energy isochronous.”
“First order time-of-flight focusing with respect to spatial coordinates,” occurs in “spatially isochronous” devices and corresponds to: dT/dx=T|x=0, dT/dy=T|y=0, dT/dα=T|α=0 and dT/dβ=T|β=0. A device may be spatially isochronous in one perpendicular direction, e.g., only T|x=0 and T|α=0.
“Spatial coordinates” is usually meant to refer to both angles to the ion path α and β and perpendicular coordinates x and y, which are measured in directions perpendicular to the ion path and in some cases within an isochronous plane.
“First order spatial focusing,” also referred to as just “focusing,” corresponds to compensation of the first order derivatives of output spatial coordinates and angles with respect to initial spatial coordinates and angles usually annotated as: x|x=0, x|α=0, α|α=0, α|x=0, etc.
“First order spatial per energy focusing,” also denoted as “chromatic” focusing and corresponds to so-called “achromatic” devices, means the compensation of the first order derivatives of the output spatial coordinates (and angles) with respect to ion energy variations−x|k=0, y|k=0, α|k=0, and β|k=0.
“Second order aberrations” are second derivatives, which are defined as analogous, but also means cross-term aberrations. A few examples of “second order aberrations” include “second and third order time-of-flight aberrations with respect to ion energy,” “second order time-of-flight aberrations with respect to spatial coordinate(s),” “second order spatial aberrations,” and “second order chromatic aberrations,” which are discussed below.
“Second and third order time-of-flight aberrations with respect to ion energy” mean d2T/dk2=T|kk and d3T/dk3=T|kkk, respectively. “Second order energy isochronous” means that both T|k=0 and T|kk=0.
“Second order time-of-flight aberrations with respect to spatial coordinate(s),” i.e. “second order spatially isochronous,” may correspond to one plane, which means that all T|x=T|α=T|xx=T|αα=T|xα=0.
“Second order spatial aberrations” correspond to x|xx; x|xα; x|α, α, etc.
“Second order chromatic aberrations” correspond to x|αk, α|αk, x|xk, α|xk, etc.
“Spatially isochronous device” means that, at the exit of the device, there exists a so-called “isochronous plane,” i.e., a plane where the ion flight time measured from some “reference plane,” which is located in front of the device, is linearly independent on both coordinates and angles of the ion trajectory. Within the description, the term “isochronous” means spatially isochronous.
“Achromatic device” is the standard term used in ion optics. It means that the device does not have linear coordinates and angular dispersion with respect to ion energy. In other words the ion coordinates and angles at the exit of the device do not depend on ion energy in the linear approximation. From general ion optics [H. Wollnik, Optics of Charged Particles, Acad. Press, Orlando, 1987], it is known that an achromatic device is an automatically spatially isochronous device with both reference plane and isochronous plane being perpendicular to the central ion path.
“Spatial focusing” means geometric focusing of an initially wide (parallel, converging or diverging) ion beam or bunch into a small-size “crossover.”
“Pulsed converter” means a device which converts a continuous or quasi-continuous ion flow into ion packets. Examples include an orthogonal accelerator or ion traps with an axial or radial pulsed ion ejection.
“Energy filtering property” is an ability to transfer ions within a limited energy range, while rejecting all other ions. As described further below in the detailed description of the invention, since curved devices create an energy dispersion somewhere inside, they allow filtering an energy range by setting a stop (a slit or an aperture) in the appropriate plane usually coinciding with the plane of geometric focusing, i.e., “crossover” plane.
“Matsuda plates” are electrodes terminating electrostatic sector fields and aligned parallel to the plane of the curved ion path. The plates are used to adjust curvature of electrostatic equipotential lines in the direction orthogonal to the ion path plane, i.e., so called “toroidal factor.”
A recent example of multi-turn instrument—MULTUM [Toyoda et. al., J. Mass Spectrom. V.38, #11 (2003), pp. 1125-1142] is built of four electrostatic sectors, arranging the ion trajectory in the shape of a figure-eight. The scheme provides for a first order time-of-flight focusing with respect to ion energy k, ion spatial coordinates x,y and corresponding angles α and β(T|k=T|x=T|α=T|y=T|β0). A high resolving power—over 300,000 is demonstrated for ion packets of sub-millimeter size and at the energy spread below 1%. To reach high resolving power ions are passed over 500 closed cycles which reduces mass range proportionally.
Multi-reflecting instruments have been arranged between two coaxial and grid-free ion mirrors [H. Wollnik, Nucl. Instr. Meth., A258 (1987) 289]. A first-order time-of-flight focusing is achieved with respect to ion energy and spatial coordinates (T|k=T|x=T|α=T|y=T|β=0). However, ultimate parameters of the scheme are limited by a pulsed ion injection. At least one mirror voltage is switched to pass ions in and out of the analyzer. Typical resolving power stays around 50,000 [A. Casares et. al., Int. J. of Mass Spectrom. 206 (2001) 267]. As in the previous case, multiple reflections automatically limit an acceptable mass range.
Most of the multi-reflecting and multi-turn instruments of the prior art do not provide for the full mass range, since ion trajectories are closed into loops. To solve the problem of mass range Nazarenko et. al. [Soviet Patent No. 1725289] in 1989 suggested a planar multi-reflecting time-of-flight (MR TOF) analyzer with a jig-saw ion path. Ions are reflected between two parallel and grid-free electrostatic mirrors while slowly drifting in the direction x of elongation of the ion mirrors—the “drift direction”. The scheme avoids repetition in ion trajectories and this way ensures full mass range of the TOF MS. However, gradual expansion of ion packets causes spatial overlapping of ion trajectories at the adjacent reflections.
To avoid ion packet spatial divergence, the inventors further improved the MR TOF scheme as disclosed in commonly assigned PCT International Publication Number WO 2005/001878 A3, filed on Jun. 18, 2004 by Anatoli Verentchikov et al., by introducing periodic lenses between the ion mirrors of a planar MR TOF MS. The lenses ensure ion confinement along the central jig-saw ion trajectory by periodic refocusing after passing through these consecutive lenses (x|α=α|x=0).
To improve aberrations of the analyzer, the inventors also suggested using an optimized geometry of planar ion mirrors. It was found that four is the minimum sufficient number of mirror electrodes to provide simultaneously:                A periodic spatial focusing of ion packets after two reflections (y|β=β|y=0);        A second order time-of-flight focusing with respect to ion spatial coordinates and energy (T|k=T|y=T|β=0; T|kk=T|yy=T|ββ=T|ky=T|kβ=T|yβ=0); and        A third order time-of-flight focusing with respect to ion energy (T|kkk=0).        
Simulations suggest that analyzer aberrations allow resolving power in excess of 100,000 at the energy spread of 7% and for ion packet dimensions of several millimeters. According to simulations, the resolving power becomes limited by two major remaining factors—aberrations appearing at the stage of ion injection into MR TOF MS and aberrations appearing in the pulsed ion source or in the pulsed converters positioned downstream of continuous ion sources. As used herein, “pulsed converters” means an orthogonal accelerator or pulse ejecting ion traps.
Let us consider the first factor limiting MR TOF MS resolution—aberrations occurring at ion injection into MR TOF MS. Earlier, in PCT International Publication Number WO 2005/001878 A3, the inventors suggested using an external ion source and injecting ions through the region of the mirror edges. Such injection inevitably introduces a number of time aberrations and spatial dispersion of ion packets as follows:                First, ions are introduced at an angle and have to be steered within the MR TOF MS to follow the central ion trajectory. The steering causes tilting of time fronts.        Second, the injected ion packets appear close to the mirror edges where the electrostatic field is distorted which may thus cause time aberrations. However, as described below with respect to FIGS. 1A-1C, this is not practical with existing sources and detectors.        Third, the remote location of the ion source shifts the intermediate time focal planes from their optimal positions at the MR TOF axis and thus compromises the initial parameters of the ion packets and degrades the overall resolving power of the MR TOF MS.        
Similar though less prominent problems appear when using internal ion sources or pulse converters. Realistic sizes of the accelerator and of the detector lead to an angled introduction of ions with subsequent ion steering. The ion packet steering remains the major source of time aberrations.
Let us consider the second factor limiting MR TOF MS resolution—time and energy spread appearing in the pulsed ion source. If assuming the source terms only, the resolution R limit could be expressed as a function of the energy tolerance (Δk/k) of TOF MS, the phase space of TOF MS (L*V), and the phase space of ion beam in the pulsed ion source (Δx*ΔV) as follows:R≦(Δk/k)*(L*V)/(Δx*ΔV)  (1)where L is an effective ion path, V is an average ion velocity and k is a mean ion energy in the TOF MS; Δx and ΔV are spatial and velocity spreads of ions in the source prior to ion acceleration and Δk is the ion energy spread after acceleration.
Multi-reflecting mass spectrometers provide an extended flight path L, which improves resolution and softens the effect on ion beam initial parameters. Still, the initial parameters of the ion packets in the source define time and energy spread of the ion packets, which is the second major limiting factor on MR TOF resolution.
The effect of the initial ion parameters becomes particularly dominating when using ion trap converters. Such traps are attractive since they are known to provide a complete (100%) conversion of continuous beam into sharp ion packets [B. Kozlov et. al. ASMS 2005, www.asms.org]. The trap converters are particularly attractive when using an MR TOF MS where injection pulses are sparse and thus the duty cycle of the alternative ion sources (like orthogonal acceleration (OA)) becomes very low. However, ions in traps are much hotter compared to OA and than ion packets characterized by significantly larger time spread.
In the past history of TOF MS, the resolution has been gradually improved while improving individual factors of the above equation (1). With the introduction of the ion mirror [U.S. Pat. No. 4,072,862, Soviet Patent No. 198034 and Sov. J. Tech. Phys. 41 (1971) 1498, Mamyrin et. al.], Mamyrin and coworkers improved energy tolerance Δk/k of TOF mass spectrometers and reached second order time-of-flight focusing with respect to ion energy (T|k=0 and T|kk=0). Similarly, to compensate for ion energy spread in the first order (T|k=0), Poschenrieder suggested a TOF MS built of electrostatic sectors [W. P. Poschenrieder, Int. J. Mass Spectrom and Ion Physics, v.9 (1972) p 357-373]. Introduction of collisional dampening of ions in gas-filled ion guides allowed improving the initial parameters of the ion beams, i.e., reducing initial spatial and velocity spreads Δx and ΔV [U.S. Pat. No. 4,963,736]. Ion guides have been employed to improve ion beam characteristics in front of orthogonal accelerators [A. V. Tolmachev, I. V. Chernushevich, A. F. Dodonov, K. G. Standing, Nucl. Instrum. Meth., B124 (1997) 112.].
The phase space of the beam has also been reduced while skimming the beam, as in the case of orthogonal accelerators (OA). A continuous ion beam is expanded and then focused into an almost parallel beam. A portion of the beam is selected through a slit. As a result, typical parameters of a continuous ion beam passing the slit are 1 mm×1 deg, which is about 3 times better than the parameters of the ion beam directly past the damping quadrupole ion guide. Ion energy spread along the TOF axis becomes 3 times lower as compared to ion energy spread at room temperature.
Another strategy of reducing the phase space of the ion packets is described in the earlier cited paper of Poschenrieder. A so-called turn-around time of ion packets is reduced by raising the strength of extracting electrostatic field. This inevitably raises the energy spread of ion packets. The excessive energy spread is filtered within an electrostatic energy filter with a curved axis. The energy filter itself is suggested as a time-of-flight analyzer. A combination of sector field with a drift region allows for the first order time-of-flight focusing with respect to ion energy and with respect to ion spatial spread and divergence. However, as was stressed before, to reach high resolving power, the acceptance of the sector TOF analyzer should be substantially reduced—energy and spatial spread should be lower than in a planar MR TOF analyzer by an order of magnitude.
Summarizing the above, multi-reflecting planar time-of-flight analyzers are suited for high resolution and full mass range measurements. Ion trap sources are particularly attractive for MR TOF since they provide an effective pulsed conversion of ion beams in spite of sparse pulsing in the MR TOF. The resolution is primarily limited by ion injection around the edges of the ion mirrors. The second limiting factor is the phase space of the ion packets in the ion source, particularly when using ion trap converters. There is a need for a solution simultaneously improving the resolving power and the sensitivity of multi-reflecting TOF mass spectrometers.